Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Celgene Europe B.V., Winthontlaan 6 N, 3526 KV Utrecht, Netherlands
Thalidomide is a powerful human teratogen, inducing a high frequency of severe and life-threatening birth defects. Thalidomide must never be used by women who are pregnant or by women who could become pregnant unless all the conditions of the Pregnancy Prevention Programme are met. The conditions of the Pregnancy Prevention Programme must be fulfilled for all male and female patients.
A female patient or a female partner of a male patient is considered to have childbearing potential unless she meets at least one of the following criteria:
For women of childbearing potential, thalidomide is contraindicated unless all of the following conditions are met:
As thalidomide is found in semen, as a precaution all male patients taking thalidomide must meet the following conditions:
The prescriber must ensure that:
Women of childbearing potential must use one effective method of contraception for at least 4 weeks before start of treatment, during treatment, and until at least 4 weeks after thalidomide treatment and even in case of dose interruption unless the patient commits to absolute and continuous abstinence confirmed on a monthly basis. If not established on effective contraception, the patient must be referred preferably to an appropriately trained healthcare professional for contraceptive advice in order that contraception can be initiated.
The following can be considered to be examples of effective methods of contraception:
Because of the increased risk of venous thromboembolism in patients with multiple myeloma (MM), combined oral contraceptive pills are not recommended (see section 4.5). If a patient is currently using combined oral contraception, she should switch to one of the effective methods listed above. The risk of venous thromboembolism continues for 4-6 weeks after discontinuing combined oral contraception.
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/ml must be performed for women of childbearing potential as outlined below. This requirement includes women of childbearing potential who practice absolute and continuous abstinence.
A medically supervised pregnancy test should be performed during the consultation, when thalidomide is prescribed or in the 3 days prior to the visit to the prescriber once the patient had been using effective contraception for at least 4 weeks. The test should ensure the patient is not pregnant when she starts treatment with thalidomide.
A medically supervised pregnancy test should be repeated every 4 weeks, including 4 weeks after the end of treatment, except in the case of confirmed tubal sterilisation. These pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.
As thalidomide is found in semen, as a precaution all male patients must use condoms during treatment, during dose interruption and for at least 7 days following discontinuation of treatment if their partner is pregnant or is of childbearing potential not using effective contraception.
Male patients should not donate semen or sperm during treatment (including during dose interruptions) and for at least 7 days following discontinuation of thalidomide.
For women of childbearing potential, prescriptions of thalidomide should be limited to a maximum of 4 weeks of treatment and continuation of treatment requires a new prescription. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of thalidomide should occur within a maximum of 7 days of the prescription.
For all other patients, prescriptions of thalidomide should be limited to a maximum of 12 weeks of treatment and continuation of treatment requires a new prescription.
Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment.
Patients should not donate blood during treatment (including during dose interruptions) and for at least 7 days following discontinuation of thalidomide.
In order to assist patients in avoiding foetal exposure to thalidomide, the Marketing Authorisation Holder will provide educational material to healthcare professionals to reinforce the warnings about the teratogenicity of thalidomide, to provide advice on contraception before treatment is started and provides guidance on the need for pregnancy testing.
The prescriber must inform male and female patients about the expected teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme and provide patients with appropriate educational brochure for patients, patient card and/or equivalent tool in accordance to the national implemented patient card system. A national controlled distribution system has been implemented in collaboration with each National Competent Authority. The controlled distribution system includes the use of a patient card and/or equivalent tool for prescribing and/or dispensing controls, and the collecting of detailed data relating to the indication in order to monitor closely the off-label use within the national territory. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of thalidomide to women of childbearing potential should occur within 7 days of the prescription and following a medically supervised negative pregnancy test result.
The use of thalidomide could be associated with menstrual disorders including amenorrhea. Amenorrhea during thalidomide therapy should be assumed to result from pregnancy, until it is medically confirmed that the patient is not pregnant. A clear mechanism by which thalidomide can induce amenorrhea is not elucidated. The reported events occurred in young (premenopausal) women (median age 36 years) receiving thalidomide for non-multiple myeloma indications, had an onset within 6 months of initiating treatment and reversed upon discontinuation of thalidomide. In documented case reports with hormone evaluation, the event of amenorrhoea was associated with decreased estradiol levels and elevated FSH/LH levels. When provided, antiovary antibodies were negative and prolactin level was within the normal range.
Myocardial infarction (MI) has been reported in patients receiving thalidomide, particularly in those with known risk factors. Patients with known risk factors for MI, including prior thrombosis, should be closely monitored and action should be taken to try to minimise all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
Patients treated with thalidomide have an increased risk of venous thromboembolism (such as deep vein thrombosis and pulmonary embolism) and arterial thromboembolism (such as myocardial infarction and cerebrovascular event) (see section 4.8). The risk appears to be greatest during the first 5 months of therapy. Thromboprophylaxis and dosing/anticoagulation therapy recommendations are provided in section 4.2.
Previous history of thromboembolic events or concomitant administration of erythropoietic agents or other agents such as hormone replacement therapy, may also increase thromboembolic risk in these patients. Therefore, these agents should be used with caution in multiple myeloma patients receiving thalidomide with prednisone and melphalan. Particularly, a haemoglobin concentration above 12g/dl should lead to discontinuation of erythropoietic agents. Action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension and hyperlipidaemia).
Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling.
Peripheral neuropathy is a very common, potentially severe, adverse reaction to treatment with thalidomide that may result in irreversible damage (see section 4.8). In a phase 3 study, the median time to first neuropathy event was 42.3 weeks.
If the patient experiences peripheral neuropathy, follow the dose and schedule modification instruction provided in section 4.2.
Careful monitoring of patients for symptoms of neuropathy is recommended. Symptoms include paraesthesia, dysaesthesia, discomfort, abnormal co-ordination or weakness.
It is recommended that clinical and neurological examinations are performed in patients prior to starting thalidomide therapy, and that routine monitoring is carried out regularly during treatment. Medicinal products known to be associated with neuropathy should be used with caution in patients receiving thalidomide (see section 4.5).
Thalidomide may also potentially aggravate existing neuropathy and should therefore not be used in patients with clinical signs or symptoms of peripheral neuropathy unless the clinical benefits outweigh the risks.
Patients should be monitored for syncope, bradycardia and atrioventricular block; dose reduction or discontinuation may be required.
Cases of pulmonary hypertension, some fatal, have been reported in patients treated with thalidomide. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during thalidomide therapy.
The incidence of neutropenia grade 3 or 4 reported as adverse reactions was higher in multiple myeloma patients receiving MPT (Melphalan, Prednisone, Thalidomide) than in those receiving MP (Melphalan, Prednisone): 42.7% versus 29.5% respectively (study IFM 99-06). Adverse reactions from post-marketing experience such as febrile neutropenia and pancytopenia were reported with thalidomide. Patients should be monitored and dose delay, reduction or discontinuation may be required (see section 4.2).
Thrombocytopenia, including grade 3 or 4 adverse reactions, has been reported in multiple myeloma patients receiving MPT. Patients should be monitored and dose delay, reduction or discontinuation may be required (see section 4.2). Patients and physicians are advised to be observant for signs and symptoms of bleeding including petechiae, epistaxis and gastrointestinal haemorrhage, especially in case of concomitant medicinal product prone to inducing bleeding (see sections 4.5 and 4.8).
Hepatic disorders, mainly abnormal liver test results, were reported. No specific pattern was identified between hepatocellular and cholestatic abnormalities, with some cases having a mixed presentation. The majority of the reactions occurred within the first 2 months of therapy and resolved spontaneously without treatment after thalidomide discontinuation. Patients should be monitored for liver function, particularly in case of pre-existing liver disorder or concomitant use of medicinal product susceptible to induce liver dysfunction (see section 4.8).
Cases of allergic reactions/angioedema and serious cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with the use of Thalidomide. Patients should be advised of the signs and symptoms of these reactions by their prescribers and should be told to seek medical attention immediately if they develop these symptoms. Thalidomide interruption or discontinuation should be considered for Grade 2-3 skin rash. Thalidomide must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS, TEN or DRESS is suspected, and should not be resumed following discontinuation for these reactions. (see sections 4.2 and 4.8).
It is very common that thalidomide causes somnolence. Patients should be instructed to avoid situations where somnolence may be a problem and to seek medical advice before taking other medicinal products known to cause somnolence. Patients should be monitored and dose reduction may be required.
Patients should be advised as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks (see section 4.7).
The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
Patients should be monitored for severe infections including sepsis and septic shock.
Cases of viral reactivation have been reported in patients receiving thalidomide, including serious cases of herpes zoster or hepatitis B virus (HBV) reactivation.
Some of the cases of herpes zoster reactivation resulted in disseminated herpes zoster, requiring a temporary hold of the treatment with thalidomide and adequate antiviral treatment.
Some of the cases of HBV reactivation progressed to acute hepatic failure and resulted in discontinuation of thalidomide. Hepatitis B virus status should be established before initiating treatment with thalidomide. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended.
Previously infected patients should be closely monitored for signs and symptoms of viral reactivation, including active HBV infection, throughout therapy.
A statistically significant increase of AML and MDS was observed in one clinical study in patients with previously untreated MM receiving the combination of melphalan, prednisone, and thalidomide (MPT). The risk increased over time and was about 2% after two years and about 4% after three years. An increased incidence of second primary malignancies (SPM) has also been observed in patients with newly diagnosed MM receiving lenalidomide. Among invasive SPMs, cases of MDS/AML were observed in patients receiving lenalidomide in combination with melphalan or immediately following high dose melphalan and autologous stem cell transplantation.
The benefit achieved with thalidomide and the risk of AML and MDS must be taken into account before initiating treatment with thalidomide in combination with melphalan and prednisone. Physicians should carefully evaluate patients before and during treatment using standard cancer screening and institute treatment as indicated.
Studies conducted in healthy subjects and patients with multiple myeloma suggest that thalidomide is not influenced to any significant extent by renal or hepatic function (see section 5.2). However, this has not formally been studied in patients with impaired renal or hepatic function; therefore patients with severe renal or hepatic impairment should be carefully monitored for any adverse events.
Thalidomide is a poor substrate for cytochrome P450 isoenzymes and therefore clinically important interactions with medicinal products that are inhibitors and/or inducers of this enzyme system are unlikely. Non-enzymatic hydrolysis of thalidomide, being the primary clearance mechanism, suggests that the potential for drug-drug interactions with thalidomide is low.
Thalidomide has sedative properties, thus may enhance the sedation induced by anxiolytics, hypnotics, antipsychotics, H1 antihistamines, opiate derivatives, barbiturates and alcohol. Caution should be used when thalidomide is given in combination with medicinal products that cause drowsiness.
Due to thalidomide’s potential to induce bradycardia, caution should be exercised with medicinal products having the same pharmacodynamic effect such as active substances known to induce torsade de pointes, beta blockers or anticholinesterase agents.
Medicinal products known to be associated with peripheral neuropathy (e.g. vincristine and bortezomib) should be used with caution in patients receiving thalidomide.
Thalidomide does not interact with hormonal contraceptives. In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 0.75 mg of ethinyl estradiol were studied. The results were similar with and without co-administration of thalidomide 200 mg/day to steady-state levels. However, combined hormonal contraceptives are not recommended due to the increased risk of venous thromboembolic disease.
Multiple dose administration of 200 mg thalidomide q.d. for 4 days had no effect on the international normalized ratio (INR) in healthy volunteers. However, due to the increased risk of thrombosis in cancer patients, and a potentially accelerated metabolism of warfarin with corticosteroids, close monitoring of INR values is advised during thalidomide-prednisone combination treatment as well as during the first weeks after ending these treatments.
Thalidomide does not interact with digoxin. In 18 healthy male volunteers, multiple dose administration of 200 mg thalidomide had no apparent effect on the single dose pharmacokinetics of digoxin. In addition, single dose administration of 0.5 mg digoxin had no apparent effect on thalidomide pharmacokinetics. It is not known whether the effect will be different in multiple myeloma patients.
Women of childbearing potential must use one effective method of contraception for at least 4 weeks before start of treatment, during treatment including during dose interruptions, and until at least 4 weeks after thalidomide treatment (see section 4.4). If pregnancy occurs in a woman treated with thalidomide, treatment must be stopped immediately and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice.
As thalidomide is found in semen, as a precaution all male patients must use condoms during treatment, during dose interruption and for at least 7 days following discontinuation of treatment when having sexual intercourse with a pregnant woman or with a woman of childbearing potential who is not using effective contraception. This applies even if the man has had a vasectomy. If pregnancy occurs in a partner of a male patient taking thalidomide, the female partner should be referred to a physician specialised or experienced in teratology for evaluation and advice.
Thalidomide is contraindicated during pregnancy and in women of childbearing potential unless all the conditions of the Pregnancy Prevention Programme are met (see section 4.3).
Thalidomide is a powerful human teratogen, inducing a high frequency (about 30%) of severe and live-threatening birth defects such as: ectromelia (amelia, phocomelia, hemimelia) of the upper and/or lower extremities, microtia with abnormality of the external acoustic meatus (blind or absent), middle and internal ear lesions (less frequent), ocular lesions (anophthalmia, microphthalmia), congenital heart disease, renal abnormalities. Other less frequent abnormalities have also been described.
It is unknown whether thalidomide is excreted in human breast milk. Animal studies have shown excretion of thalidomide in breast milk. Therefore breast-feeding should be discontinued during treatment with thalidomide.
A study in rabbits demonstrated no effect on fertility indices in males or females although testicular degeneration was observed in males.
Thalidomide Celgene as per the recommended posology has minor or moderate influence on the ability to drive and use machines.
Thalidomide may cause fatigue (very common), dizziness (very common), somnolence (very common) and blurred vision (common) (see section 4.8). Patients should be instructed not to drive cars, use machines or perform hazardous tasks while being treated with thalidomide if they feel tired, dizzy, sleepy or have blurred vison.
Most patients taking thalidomide can be expected to experience adverse reactions. The most commonly observed adverse reactions associated with the use of thalidomide in combination with melphalan and prednisone are: neutropenia, leukopenia, constipation, somnolence, paraesthesia, peripheral neuropathy, anaemia, lymphopenia, thrombocytopenia, dizziness, dysaesthesia, tremor and peripheral oedema.
In addition to the adverse reactions outlined above, thalidomide in combination with dexamethasone in other clinical studies led to the very common adverse reaction of fatigue; common adverse reactions of transient ischaemic event, syncope, vertigo, hypotension, mood altered, anxiety, blurred vision, nausea and dyspepsia; and uncommon adverse reactions of cerebrovascular accident, diverticular perforation, peritonitis, orthostatic hypotension and bronchitis.
The most clinically important adverse reactions associated with the use of thalidomide in combination with melphalan and prednisone or dexamethasone include: deep vein thrombosis and pulmonary embolism, peripheral neuropathy, severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, syncope, bradycardia, and dizziness (see sections 4.2, 4.4 and 4.5).
Table 3 contains only the adverse reactions for which a causal relationship with medicinal product treatment could reasonably be established observed in the pivotal study and from post-marketing experience. Frequencies given are based on the observations during a pivotal comparative clinical study investigating the effect of thalidomide in combination with melphalan and prednisone in previously untreated multiple myeloma patients.
Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 3. Adverse drug reactions (ADRs) reported in pivotal clinical study with thalidomide in combination with melphalan and prednisone and from post marketing use:
Common: Pneumonia
Not Known: Severe infections (e.g. fatal sepsis including septic shock)†, Viral infections, including herpes zoster and hepatitis B virus reactivation†
Common: Acute myeloid leukaemia*^
Uncommon: Myelodysplastic syndrome*^
Not Known: Tumour lysis syndrome†
Very Common: Neutropenia, Leukopenia, Anaemia, Lymphopenia, Thrombocytopenia
Common: Febrile neutropenia†, Pancytopenia†
Not Known: Allergic reactions (hypersensitivity, angioedema, urticaria)†
Not Known: Hypothyroidism†
Common: Confusional state, Depression
Very Common: Peripheral neuropathy*, Tremor, Dizziness, Paraesthesia, Dysaesthesia, Somnolence
Common: Convulsions†, Abnormal coordination
Not Known: Posterior reversible encephalopathy syndrome (PRES)*†, Worsening of Parkinson’s disease symptoms†
Common: Hearing impaired or deafness†
Common: Cardiac failure, Bradycardia
Uncommon: Myocardial infarction†, Atrial fibrillation†, Atrioventricular block†
Common: Deep vein thrombosis*
Common: Pulmonary embolism*, Interstitial lung disease, Bronchopneumopathy, Dyspnea
Not Known: Pulmonary hypertension†
Very Common: Constipation
Common: Vomiting, Dry mouth
Uncommon: Intestinal obstruction†
Not Known: Gastrointestinal perforation†, Pancreatitis†, Gastrointestinal haemorrhage†
Not Known: Hepatic disorders†
Common: Toxic skin eruption, Rash, Dry skin
Not Known: Stevens-Johnson syndrome*†, Toxic epidermal necrolysis*†, Drug reaction with eosinophilia and systemic symptoms*†, Leukocytoclastic vasculitis†
Common: Renal failure†
Not Known: Sexual dysfunction†, Menstrual disorders including amenorrhea†
Very Common: Peripheral oedema
Common: Pyrexia, Asthenia, Malaise
* see section 4.8 description of selected adverse reactions
† identified from post marketing data
^ Acute myeloid leukaemia and Myelodysplastic syndrome were reported in one clinical study in patients with previously untreated MM receiving the combination of melphalan, prednisone and thalidomide (MPT)
Adverse reactions for haematological disorders are provided compared to the comparator arm, as the comparator has a significant effect on these disorders (Table 4).
Table 4. Comparison of haematological disorders for the melphalan, prednisone (MP) and melphalan, prednisone, thalidomide (MPT) combinations in study IFM 99-06 (see section 5.1):
| n (% of patients) | ||
|---|---|---|
| MP (n=193) | MPT (n=124) | |
| Grades 3 and 4* | ||
| Neutropenia | 57 (29,5) | 53 (42,7) |
| Leukopenia | 32 (16.6) | 32 (25,8) |
| Anaemia | 28 (14,5) | 17 (13,7) |
| Lymphopenia | 14 (7,3) | 15 (12,1) |
| Thrombocytopenia | 19 (9,8) | 14 (11,3) |
* WHO Criteria
Additional adverse reactions from post-marketing experience with thalidomide and not seen in the pivotal study include febrile neutropenia and pancytopenia.
The risk of intra-uterine death or severe birth defects, primarily phocomelia, is extremely high. Thalidomide must not be used at any time during pregnancy (see sections 4.4 and 4.6).
An increased risk of venous thromboembolism (such as deep vein thrombosis and pulmonary embolism) and arterial thromboembolism (such as myocardial infarction and cerebrovascular event) has been reported in patients treated with thalidomide (see section 4.4).
Peripheral neuropathy is a very common, potentially severe, adverse reaction of treatment with thalidomide that may result in irreversible damage (see section 4.4). Peripheral neuropathy generally occurs following chronic use over a period of months. However, reports following relatively short-term use also exist. Incidence of neuropathy events leading to discontinuation, dose reduction or interruption increases with cumulative dose and duration of therapy. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all.
Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior leukoencephalopathy syndrome (RPLS)
Cases of PRES/RPLS have been reported. Signs and symptoms included visual disturbance, headache, seizures and altered mental status, with or without associated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. The majority of the reported cases had recognized risk factors for PRES/RPLS, including hypertension, renal impairment and concomitant use of high dose corticosteroids and/or chemotherapy.
AML and MDS were reported in one clinical study in patients with previously untreated multiple myeloma receiving the combination of melphalan, prednisone, and thalidomide (see section 4.4).
Serious cutaneous reactions including Stevens-Johnson syndrome TEN and DRESS have been reported with the use of thalidomide therapy. If Stevens-Johnson syndrome, TEN or DRESS is suspected, use of thalidomide should not be resumed (see section 4.2 and 4.4).
The adverse reaction profile reported in patients >75 years of age treated with thalidomide 100 mg once daily was similar to the adverse reaction profile observed in patients ≤75 years of age treated with thalidomide 200 mg once daily (see Table 3). However, patients with age >75 years are potentially at risk for a higher frequency of serious adverse reactions.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
